This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation activity. The polyamines putrescine, spermidine and spermine are important for cell growth and differentiation; ertain types of cancer and parasitic diseases are associated with elevated levels of polyamines. Maintaining the polyamine levels in the cells by regulating the polyamine biosynthetic pathway is a promising tool for anti-cancer and anti-parasitic therapy. AdoMetDC catalyses the conversion of S-Adenosylmethionine (AdoMet) to decarboxylated S-Adenosylmethionine (dcAdoMet). The propylamine group of dcAdoMet is transferred to putrescine and spermidine to form spermidine and spermine respectively. AdoMetDC is at a key branch point in the pathway and dcAdoMet is committed to polyamine biosynthesis. The polyamine putrescine activates the autoprocessing and decarboxylation reactions of AdoMetDC. Previous crystal structures have a molecule of putrescine bound in the putrescine binding site and identify the key interactions with the enzyme. The crystal structures of human AdoMetDC bound to various inhibitors were also solved previously. The primary goal of the project is to obtain the crystal structure of AdoMetDC in parasites and the complexes of human AdoMetDC with various inhibitors in search of potential lead compounds for drug design. In addition, the crystal structures of the mutants in the putrescine binding site of human AdoMetDC would provide insights into the mechanism of activation.